From mice to men, research in the next few decades may lead to
therapies that will dramatically extend our lifespans.

Biologist Aubrey de Grey is developing therapies designed to
postpone aging. His test subjects may still be mice, but he argues
“there are no absolutely fundamental breakthroughs that we still
need” in order to make the jump to humans.

So how long can you and I expect to live?

“At this point I think it’s fair to say there’s a good chance
that people who are alive today, and are still young, children
today, there’s a good chance that they have no upper limit on their
lifespan,” asserts de Grey in a recent MemeBox interview

His roadmap to longevity starts in the mind:

“I think in the next 5 years we have a very good chance of
seeing a complete phase change in people’s attitude to what aging
is. In other words, to the distinction, or lack of it, between
aging and age-related diseases.”

The signs are all around us and yet, rather surprisingly, there
is very little public discussion of an issue that is going to have
profound moral, ethical, and political ramifications for all of
society.

Last week, I discussed why the future is accelerating
and before that, I encouraged readers when thinking about the
future to “think 10X, not 10%”; and the more I
think about health care and human longeveity, the more I think both
of these lines of thought apply to this field in particular.
(cont.)

A: I’m a biologist, mainly, and I’m focused on the development
of future therapies that will be able to postpone human aging a
very great deal. By postpone, what I really mean is, repair the
accumulating molecular and cellular damage that causes aging, and
really is aging. The various things that happen, the side effects
of our normal metabolic operations, so to speak, throughout our
lives that will eventually cause things to go wrong with us.

A: The main thing that it really has to do is to grow. At the
moment we’re not nearly big enough. There’s masses of research that
needs to be done, that isn’t being funded by anybody else, because
people think it’s too ambitious or they don’t understand the goals
or whatever, and it’s not being funded by us because we don’t have
the money yet. My my main purpose, my main focus at the moment is
to expand the foundation, to get more money in so that we can put
more money out.

One of the themes on Future Blogger and for fans of accelerating
change in general is life extension and the prospect of relative
immortality.
We covered this topic in our very first interview with
Aubrey de Grey and Dick
Pelletier has addressed it many times. One of the core
arguments in this debate is that, regardless of increasing life
expectancy rates, humans have an upper limit. This is probably best
categorized as the Hayflick
limit argument . That there is a maximum number of years that a
human can live and if nothing gets to you before reaching that
threshhold, when you do, that’s it – it’s over. That limit is about
120 years of age, with the oldest documented lifespan being the 122
attained by Jean Calumet

Increases in life expectancy are ultimately discounted by this
assumption. In response to Jack Uldrich’s
recent piece on the prospect of living to 1000, John
Frink correctly points out that the radical increase in life
expectancy that developed societies have experienced over the last
170 years or so (roughly doubling) is largely due to advances in
health/medicine and hygiene. He cites the vast reduction in the
infant mortality rate as being of particular note. But that is more
reflective of initial gains and merely part of a larger trend at
work. (cont.)

Accenture
is just months away from releasing a product it calls the
Persuasive Mirror,
a product that allows you to view a simulation of your face as it’s
projected to look 6 months in the future. Equipped with sensors and
software capable of extrapolating your face based on consistent
visual input, the mirror accomplishes its work automatically.

At a touch of the screen, the Persuasive Mirror offers
suggestions about how to improve your look. For example, it may
tell you to “walk to work today” or “stay away from junk foods for
the next week.”

Accenture believes that such “continuous visual feedback on
behavior” will have a positive effect on the way we manage our
lifestyles. In other words, looking our future face directly in the
face is likely to frighten us into healthier behavior.

My opinion is that, while a bit unnerving, such products are
probably inevitable in a world of constant innovation and
inexorable quantification of everything. Just as futurists
extrapolate the state of larger systems in order to generate
best-guess simulations, the Persuasive Mirror does this for the
smaller facial system. As we continue to get better at the
real-time quantification of the body, the health benefits will
become obvious and so we’ll continue on our path down the rabbit
hole. This will likely result in sensor networks embedded
throughout and around our bodies, similar to the pervasive sensing
that futurists argue will saturate our environment. After all, we
are part of that environment.

Could you come face to face with a mirror that more or less accurately predicts your future appearance and choose not to look?

Yes. Too much information can be a bad thing. I don’t want to constantly live in fear.

I’d hold out as long as possible.

No. It’s a great idea and a wonderful tool to help me live into a healthier future.

Cellular senescence is regarded as a tumor suppressor mechanism:
damaged cells permanently leave the cell cycle (preventing tumor
initiation), and also secrete factors that trigger both tissue
repair and inflammation in the vicinity. This is probably good at
first but bad later on: persistent senescent cells also secrete
growth factors and metalloproteases that degrade the tissue
microenvironment and encourage nearby preneoplastic cells to
progress into full-blown tumors. Thus, senescence has been
implicated in late-life cancer and age-related decline in tissue
function.

The “damage” in question is usually genotoxic in nature:
telomere shortening, indicating that a cell has undergone many
rounds of potentially mutagenic cell division, or high levels of
DNA damage such as that resulting from
ionizing radiation or exposure to chemical clastogens. Oncogene
expression probably also induces senescence via DNA damage, by triggering over-firing of replication
origins and generating broken ends and weird chromatin structures
that are interpreted as damage.

Now it appears that falling cellular ATP levels may also result in cellular senescence.
Unterluggauer et al. report that inhibition of
glutaminolysis (preventing cells from generating ATP from glutamine, an unglamorous and occasionally
overlooked pathway that is nonetheless an important energy source
in many cellular lineages) results in increased senescence in human
vascular endothelial cells (HUVECs): (cont.)

It is widely accepted that stem cells are involved in tissue
regeneration. It is also widely accepted that (in most organs) stem
cells are vanishingly rare. So: if there doesn’t happen to be a
stem cell adjacent to a site of damage, how can stem cells be
involved in the process of tissue repair?

One possible answer: There might be more stem cells than we
think, because we’ve been missing them for some reason. This
possibility (”both”) is strongly supported by the recent findings
of Zuba-Surma et al., who have discovered a
population of tiny pluripotent cells (termed, appropriately, very
small embryonic-like, or VSELs) scattered throughout the body.

Very small embryonic-like stem cells in adult
tissues—Potential implications for aging

Recently our group identified in murine bone marrow (BM) and
human cord blood (CB), a rare population of very small
embryonic-like (VSEL) stem cells. We hypothesize that these cells
are deposited during embryonic development in BM as a mobile pool
of circulating pluripotent stem cells (PSC) that play a pivotal
role in postnatal tissue turnover both of non-hematopoietic and
hematopoietic tissues.(cont.)

Chronic stress has been associated with decreased telomere
length in lymphocytes. The association is robust and has been
observed in multiple studies, including one that looked at stress
in addition to other risk factors for
cardiovascular disease (CVD), so it appears that lymphocyte
telomeres are a useful biomarker for some convolution of age and
lifetime stress level. The question still remains, however, whether the relationship
is correlative or causative. Do stress and other lifestyle factors
somehow cause shortened telomeres, or are the two phenomena
otherwise-unrelated indications of some common underlying
cause?

One of the “trivial” explanations for a causative relationship,
usually advanced by critics who aren’t particularly impressed by
the initial findings, is that stressed-out or otherwise unhealthy
people are more vulnerable to infection than their serene, healthy
counterparts. Chronic infection requires increased production of
lymphocytes, which overworks the stem cell compartment from which
these cells are derived; increased cell divisions leads to
decreased telomere length — a perfectly satisfactory explanation
for the observation.

If that is true, then chronic infection in the absence of
lifestyle risk factors should cause telomere shortening on its own
(let’s stipulate for the moment that stress increases
susceptibility to disease, an idea supported by my own anecdotal
experience of college finals). Ilmonen et
al. have demonstrated that this is indeed the case, at
least in mouse: (cont.)

Stress resistance at the cellular level is correlated with
longevity at the organismal level, to such an extent that one can
screen for longevity mutants by first identifying
stress-resistant animals. Conversely, the cells of prematurely
aging mutants tend to be
hypersensitive to stress. The idea here is that longevity is
controlled in part by basal and inducible molecular defenses like
antioxidants and chaperones, and that high levels of such factors
confer both stress resistance and enhanced longevity.

What’s interesting about this pattern is that it seems to apply
to a wide range of multiple stresses, with very different physical
bases: oxidation, irradiation, starvation, heavy metal toxicity,
and temperature, to name a few. Without a great deal of
experimental proof to support it, one can imagine some central
homeostatic integrator of cellular well-being, upon which all
manner of perturbations might impinge and which might in turn
control both the appropriate defensive responses and factors that
determine longevity.

It would therefore come as a surprise if a long-lived organism
turned out to be unusually sensitive to stress — and in particular,
sensitive to particular stresses. In one fell swoop, this
would falsify both the general, well-accepted correlative pattern
(stress resistance = longevity) and the somewhat more fanciful
model of a central homeostatic integrator.

align=”right” width=”100”>Lo, the naked mole rat,
Heterocephalus glaber. A eusocial rodent roughly
intermediate in size between a mouse and a rat (depending on where
you shop), and slightly less aesthetically pleasing than an
overcooked boudin blanc with teeth, the naked mole rat has
recently drawn the attention of model-hungry biogerontologists
worldwide: Perhaps because of the
quirky selection pressures on eusocial animals, H.
glaber is unusually long-lived compared to animals of similar
size and body plan (like mice and rats). Like, ten times
longer-lived. So, compared to mice and rats, mole rats should be
much more resistant to all stresses, right? (cont.)

My post last week on the Demise of Death received so many thought provoking comments that I feel compelled to further the discussion in another post. The new information and perspectives contained in the the comments have transformed the way I intend to approach parts of the debate. With such a fertile discussion ground, I felt I would be remiss if I did not give attention and thanks to several of the eloquently expressed ideas.

Here’s the point-by-point update:

Nanotech & Biotech Will Not Necessarily End Death: That death may remain even if aging is cured was a point raised by a few of the commentors. If our bodies did not deteriorate into death, fatal accidents, acts of violence etc. could still bring about mortality. I realize that my rationale for thinking we may be able to conquer death altogether was somewhat obscure in my first post. One theory proposed by futurists and transhumanists, is that to truly conquer aging, we will not be able to rely merely on stem cells, genetic therapies and drugs.

These treatments can, the theory argues, only go so far to combat cellular deterioration. If we are to truly end, and not merely delay aging, we would eventually have to develop nanobots capable of precisely repairing cells. My own logic followed that if we are able to create effective cellular-repair nanobots, we will have mastered nanotechnology and it will serve a number of other functions beyond cellular repair.

Prolific poster Dick Pelletier has pointed out a few times that if nanobot technology were mastered, we could, in theory, surround ourselves in a sort of thin nanobot shield that could, in theory, protect us from violence and accident. Perhaps I have taken this rationale too far. It does not logically follow that by ending aging we will necessarily end death by accident or violence, but I think it is at least a reasonable possibility.

Taking Control of Your Fate Opens Pandora’s Box: Let us consider my original conjecture is incorrect and that we will be able to bring an end to aging, but not death by accident or violence. If this becomes true, we will, in effect be gaining a greatly extended life at the expense of knowing that death will certainly come either by violence, violent accident or suicide. I cannot help but think these are all troubling ends.

Admittedly, most deaths now are troubling. Death by disease and aging is most often the end of a long, painful, degrading, messy battle. But, at present, we can at least hope to be one of the lucky few to die comfortably, unknowingly in their sleep. This hope will be eliminated if aging is defeated.

Even to me the benefits outweigh the downsides, but it is deeply disturbing to know you will one day kill yourself if you aren’t hit by a bus or murdered first. This is in part what I meant when I wrote that I considered myself a part of nature and do not wish to be removed from the natural process. Taking your fate out of the hands of nature results in some very difficult decisions.

Accepting Suicide? This idea of death occurring either by chance or choice is tied to another point raised in the comments. Johnfrink said, “I’m pretty sure if we conquer death eternal life will not be forced on anybody.” And I am inclined to agree. It is unlikely that in a future without aging, omniscient police will parole the streets taking into custody all those thinking of ending it all. But that doesn’t mean suicide will be any more desirable than it is today.

Welcome to the first installation of Hourglass, a blog carnival
devoted to the biology of aging. This first issue corresponds with
the second blogiversary
of Ouroboros, but mostly I consider it a
celebration of the excellent (and growing) community of
bloggers who are writing about biogerontology, lifespan extension
technologies, and aging in general.

Without further ado, then, let’s get started:

Reason at Fight Aging! reports on AnAge, a
curated database of longevity, aging, and life history in a wide
range of animals. The database contains information about average
and maximum longevity within species, and also cool features like
lists of the “world-record” holders for the longest-lived organisms
on the planet. AnAge will be a great tool for anyone interested in
studying
evolution of negligible senescence or exploiting
lifespan diversity across related species to learn about
mechanisms of aging. For those who are interested in databases of
this kind, AnAge is a component of a larger project, the Human Ageing Genomic
Resources.

The most widely studied technique for
extending the lifespan of diverse animals is calorie restriction (CR),
whose benefits in humans are still under careful study. One of the
disadvantages of studying humans, of course, is that you can’t keep
them in completely controlled environments, free from temptation to
cheat on their defined diets — but this may be more than adequately
compensated by the main advantage of human subjects, namely, that
they can tell you how they’re feeling about the study while it’s
underway. Over at Weekly Adventures
of a Girl on a Diet, Elizabeth Ewen describes
her experiences as a subject in the CALERIE study, a large-scale test of the effects
of CR on humans (we’ve discussed CALERIE
here before). In her post, Elizabeth describes the CALERIE study in detail, and also critically assesses
some of its specific features — something that no mouse, however
talented, could ever do. (cont.)

Scientists like Aubrey de Grey offer
convincing arguments that advances in medical technologies will one
day bring us to the point where we can effectively solve death. But
will we and should we choose to do so? You make the call. :)

Would you choose to live forever if the technology that prevented death existed?

Yes. Absolutely. Death is a disease that should be cured.

No way. Death is natural and who are we to change the rules?

Maybe. I need a few more years to contemplate that. Cost, my evolving memeplex, and the people around me will certainly figure in.